Choroidal neovascularization leads to hemorrhage and fibrosis, with resultant visual loss in a number of eye diseases, including macular degeneration, ocular histoplasmosis syndrome, myopia, and inflammatory diseases. Age-related macular degeneration (AMD) is the leading cause of new blindness in the elderly, and choroidal neovascularization is responsible for 80% of the severe visual loss in patients with this diseases. Although the natural history of the disease is eventual quiescence and regression of the neovascularization process, this usually occurs at the cost of sub-retinal fibrosis and vision loss.
Current treatment of AMD relies on occlusion of the blood vessels using laser photocoagulation. However, such treatment requires thermal destruction of the neovascular tissue, and is accompanied by full-thickness retinal damage, as well as damage to medium and large choroidal vessels. Further, the subject is left with an atrophic scar and-visual scotoma. Moreover, recurrences are common, and visual prognosis is poor.
Developing strategies have sought more selective closure of the blood vessels to preserve the overlying neurosensory retina. One such strategy is photodynamic therapy, which relies on low intensity light exposure of photosensitized tissues to produce photochemical effects. Photosensitizing dyes are preferentially retained in tumors and neovascular tissue, which allows for selective treatment of the pathologic tissue. As a result of the invention, PDT may be used to cause vascular occlusion in tumors by damaging endothelial cells, as well as a direct cytotoxic effect on tumor cells.
Photodynamic therapy of conditions in the eye characterized by neovascularization has been attempted over the past several decades using the conventional porphyrin derivatives such as hematoporphyrin derivative and Photofrin porfimer sodium. Problems have been encountered in this context due to interference from eye pigments. In addition, phthalocyanine has been used in photodynamic treatment.
A newer photosensitizer, a member of the group designated "green porphyrins", is in the class of compounds called benzoporphyrin derivatives (BPD). This photosensitizer has also been tested to some extent in connection with ocular conditions. For example, Schmidt, U. et al. described experiments using BPD coupled with low density lipoprotein (LDL) for the treatment of Greene melanoma (a nonpigmented tumor) implanted into rabbit eyes and achieved necrosis in this context (IOVS (1992) 33:1253 Abstract 2802). This abstract also describes the success of LDL-BPD in achieving thrombosis in a corneal neovascularization model. The corneal tissue is distinct from that of the retina and choroid.
The present applicants have described treating choroidal neovascularization using LDL-BPD in several abstracts published Mar. 15, 1993. These abstracts include those by Schmidt-Erfurth, U. et al. (abstract 2956); by Haimovici, R. et al. (abstract 2955); and by Walsh, A. W. et al. (abstract 2954). In addition, Lin, S. C. et al. described photodynamic closure of choroidal vessels using liposomal BPD in (abstract 2953). All of the foregoing are published in IOVS (1993) 34:1303. An additional abstract of the present applicants describing LDL-BPD to inhibit choroidal neovasculature is by Moulton, R. S. et al. (abstract 2294), IOVS (1993) 34:1169.
The green porphyrins offer advantages in their selectivity for neovasculature. The present applicants have further determined that coupling of the green porphyrins to a carrier such as LDL or as contained-in a liposomal formulation provides an advantageous delivery method for the drug to the desired ocular location.